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PubMed1994

The gene upstream of DmRP128 codes for a novel GTP-binding protein of Drosophila melanogaster.

Upstream of the gene coding for the second-largest subunit of RNA polymerase III (DmRP128) we have found another gene (128up), which is transcribed in the same direction as the RNA polymerase gene. The intergenic distance between the 3' end of 128up mRNA and the 5' end of DmRP128 mRNA is only about 100 bp. Transcripts of 128up are present at a much higher level than DmRP128 RNA in Drosophila Schneider 2 cells, embryos, and adult flies. Two transcription start points, seven nucleotides apart, are found for 128up compared to multiple scattered starts for DmRP128. Sequence analysis of 128up cDNA reveals that the gene codes for a 41 kDa protein with homology to GTP-binding proteins and matching four of the structural sequence motifs characteristic of the superfamily of GTPases. Bacterially expressed 128up protein fused to maltose-binding protein specifically binds GTP. Sequences closely related to the 128up protein are found in species as distant as Halobacterium, yeast or mouse; the murine protein is 80% identical to 128up. This evolutionary conservation is indicative of an important, but as yet unknown, physiological role. In accordance with the sequence conservation, antibodies against 128up specifically cross-react with mouse 3T3 cells and human Hep2 cells where the subcellular localization of the protein is predominantly perinuclear. We propose that 128up is a member of a novel class of GTP-binding proteins.

Amino Acid Sequence↗
PubMed1994

Homologs of the yeast neck filament associated genes: isolation and sequence analysis of Candida albicans CDC3 and CDC10.

Morphogenesis in the yeast Saccharomyces cerevisiae consists primarily of bud formation. Certain cell division cycle (CDC) genes, CDC3, CDC10, CDC11, CDC12, are known to be involved in events critical to the pattern of bud growth and the completion of cytokinesis. Their products are associated with the formation of a ring of neck filaments that forms at the region of the mother cell-bud junction during mitosis. Morphogenesis in Candida albicans, a major fungal pathogen of humans, consists of both budding and the formation of hyphae. The latter is thought to be related to the pathogenesis and invasiveness of C. albicans. We have isolated and characterized C. albicans homologs of the S. cerevisiae CDC3 and CDC10 genes. Both C. albicans genes are capable of complementing defects in the respective S. cerevisiae genes. RNA analysis of one of the genes suggests that it is a regulated gene, with higher overall expression levels during the hyphal phase than in the yeast phase. Not surprisingly, DNA sequence analysis reveals that the proteins share extensive homology at the amino acid level with their respective S. cerevisiae counterparts. Related genes are also found in other species of Candida and, more importantly, in filamentous fungi such as Aspergillus nidulans and Neurospora crassa. A database search revealed significant sequence similarity with two peptides, one from Drosophila and one from mouse, suggesting strong evolutionary conservation of function.

Amino Acid Sequence↗
PubMed1991

Regulation of replication of plasmid R1: an analysis of the intergenic region between copA and repA.

The synthesis of the rate-limiting RepA replication initiator protein of plasmid R1 is negatively controlled by an antisense RNA, CopA. The regulation is posttranscriptional and involves an inhibitory effect on RepA translation mediated by the binding of CopA to its target (CopT) in the leader region of the RepA mRNA. The evolutionary conservation of the intergenic region between the copA gene and the repA reading frame among plasmids related to R1 may be indicative of an important function in this regulation. One possibility is that sequences/structures in this region might be required for the presumed distal effect of CopAQCopT binding. We have performed a mutational analysis of this region, starting with a mutant repA-lacZ fusion plasmid that shows decreased RepA-LacZ synthesis compared to a wild-type construct, and have identified five compensatory mutations that increase repA-lacZ expression. Two of these were single base-pair substitutions in the copA promoter leading to a decrease in CopA transcription. The other three mutations increased RepA synthesis in the presence as well as in the absence of functional CopA. Reconstructed plasmids carrying these mutations--in conjunction with the original down-mutation or in an otherwise wild-type background--show the expected increase in copy number. The effect of two of these mutations is consistent with the destabilization of a putative secondary structure which may be responsible for the normally low translation rate of the RepA reading frame. The implications of the types of mutations found in this study, as well as the absence of other classes of mutations, are discussed in terms of alternative possible models of CopA-mediated inhibition of RepA synthesis.

Bacterial Proteins↗
PubMed1995

Reversions to respiratory competence of omnipotent sup45 suppressor mutants may be caused by secondary sup45 mutations.

The molecular nature of the sup45 respiratory deficient omnipotent suppressor, and of three reversions to respiratory competence which removed the suppressor effect of the initial mutation, was examined. All reversions were caused by secondary sup45 mutations which indicates a direct connection between sup45 "respiratory" and "translational" functions. Computer analysis showed the local changes of Sup45 protein characteristics in the suppressor strain and revertants in comparison to the wild-type protein. The distribution of mutant sites in relation to evolutionary conserved, and tentatively functional, regions in the Sup45 protein is discussed.

Amino Acid Sequence↗
PubMed1986

Evolution of Y chromosomal lampbrush loop DNA sequences of Drosophila.

The evolutionary conservation of Y chromosomal DNA sequences of Drosophila hydei in different species of the genus Drosophila was studied by in situ hybridization and on genomic DNA blots of restriction enzyme digested DNA. We demonstrated that Y specific DNA sequences, which form major parts of lampbrush loops related to the male fertility genes, are only retained in a few closely related species during evolution. Other Y chromosomal DNA sequences, also present in lampbrush loops but with homology to autosomal and X chromosomal locations, were found in distant species. We propose a model for the evolution of the Y chromosomal lampbrush loops.

Animals↗
PubMed1984

Escherichia coli and Pseudomonas putida RNA polymerases display identical contacts with promoters.

Methylation protection experiments with four promoters (P1 and P2 of the pBR322 plasmid, lacUV5 and lambda P0) have shown that the RNA polymerases from Escherichia coli and Pseudomonas putida, while differing in the primary structure of the subunits involved in DNA binding, display identical patterns of DNA contacts. Nor do these enzymes differ in covalent cross-linking patterns with a partially apurinized promoter. We conclude that the two RNA polymerases have very similar structures of DNA binding centers. The evolutionary conservation of this structure may account for the fact that diverse RNA polymerases often recognize and efficiently use promoters of distant bacterial species.

Bacteriophage lambda↗
PubMed1992

Y enriched and Y specific DNA sequences from the genome of the Mediterranean fruit fly, Ceratitis capitata.

DNA sequences that are enriched or specific to the genome of the male medfly, Ceratitis capitata, have been isolated using a differential hybridization approach. Twelve phage clones from a genomic library have been identified that consistently display more intense hybridization with a genomic DNA probe from males as opposed to one from females. Southern DNA blot analysis reveals that these recombinant clones contain at least one EcoRI fragment that is either specific to the male genome, or more highly represented in it, as compared with the female genome. These EcoRI fragments, when used as probes, all generate a similar pattern of intense multiple bands in genomic DNA of males. This suggests the presence of repetitive sequences that are at least partially homologous in these regions of the genome that are specific to or enriched in males. In situ hybridization to mitotic chromosomes confirms a Y chromosomal origin for the male specific repetitive sequences. Data on the genomic organization, representation and evolutionary conservation of these sequences that are specific to or enriched in males are presented. Studies of the genomic organization and representation of flanking sequences that are not male specific are presented as well.

Animals↗
PubMed1994

Human homolog of a mouse sequence from the dystonia musculorum locus is on chromosome 6p12.

Dystonia musculorum is a hereditary neurodegenerative disease in mice that affects sensory neurons. In an effort to clone the gene responsible for this disorder, we have assembled a genomic contig spanning 75 kb of the dystonia musculorum (dt) locus. Within this genomic contig, we have identified a small restriction fragment that shows evolutionary conservation to rat, hamster, rabbit, and human genomic DNA. Using this mouse sequence, we have cloned the conserved human genomic fragment. Sequence analysis of the mouse and human genomic fragments revealed that they share a sequence similarity of 82% over 175 bp. A panel of human/rodent somatic cell hybrids was used to map the human genomic sequence to Chromosome (Chr) 6, and high-resolution in situ hybridization (FISH) allowed it to be sublocalized to 6p12. The human homolog of the mouse Bpag1 gene, a gene tightly linked to the mouse dt gene, also maps to Chr 6. Thus, this comparative mapping reveals a new region of conserved synteny between the chromosomes of mouse and human. Mapping the human homolog of the mouse dt gene enables us to initiate linkage studies to identify neurodegenerative disorders that may be caused by mutations in this gene.

Animals↗
PubMed1977

Serum esterase genetics in rabbits. IV. The prealbumin and beta-globulin systems.

Discontinuous starch gel electrophoresis revealed a fourth allele of rabbit pre-albumin serum esterase at locus Est-2. This allele is designated Est-2f and appears to be silent. In addition to the prealbumin serum esterases, another serum esterase system was studied in rabbits. This system is localized in the beta-globulin region. Genetic analysis indicated that one locus with two codominant alleles controls the variation in this region. Linkage of this system with Est-1 and Est-2 of the prealbumin serum esterases was demonstrated. Comparison of the arrangement of these esterase loci on linkage group VI with the esterase loci on chromosome 8 of the mouse gives additional support for the theory of evolutionary conservation of chromosomal segments coding for mammalian esterases.

Alleles↗
PubMed1992

Translational readthrough at nonsense mutations in the HSF1 gene of Saccharomyces cerevisiae.

The HSF1 gene of Saccharomyces cerevisiae directs the synthesis of the heat shock transcription factor, HSF. The gene is essential; disruption mutations are lethal. Using a plasmid shuffle screen, we isolated mutations in the HSF1 gene after in vitro mutagenesis of plasmid DNA with hydroxylamine. From a collection of both conditional (temperature-sensitive) and unconditional lethal mutations, we recovered mutations that map exclusively to the 5' half of the gene. All are nonsense mutations, including conditional mutations that map 5' to the portion of the HSF1 gene that encodes the DNA-binding domain of the transcription factor. For one such mutation, we demonstrated that the nonsense mutation is subject to translational readthrough, even though there are no known nonsense suppressors in the genetic background of our strain. Our results suggest that the HSF protein is highly tolerant of amino acid changes, a conclusion that is consistent with the very low degree of evolutionary conservation among HSF proteins. Our results also suggest that translational readthrough occurs with moderate efficiency in yeast, particularly when the terminator codon is followed immediately by an A or C residue. This result illustrates that the inference of gene function from mutant phenotype depends critically upon the analysis of a true null allele, and not merely an amber or ochre allele.

Amino Acid Sequence↗
PubMed1983

Oncogenes in retroviruses and cells.

Oncogenes are genes that cause cancer. Retroviruses contain oncogenes and cause cancer in animals and, perhaps, in man. The viruses have appropriated their oncogenes from normal cellular DNA by genetic recombination. Correspondingly, uninfected vertebrate cells contain a family of evolutionary conserved cellular oncogenes. Retrovirus infection, introducing additional viral oncogenes into the cells, as well as carcinogen-mediated activation of cellular oncogenes may both lead to increased synthesis of oncogene encoded transforming proteins which convert normal cells to tumor cells. Unique retroviruses of human origin have recently been identified. They may, on occasion, directly cause tumors in man. However, the general significance of retroviruses may better be illustrated by their remarkable genetic composition which allows them to promote tumor growth by a variety of genetic mechanisms.

Animals↗
PubMed1992

Human cyclin B1 gene (CCNB1) assigned to chromosome 5 (q13-qter).

Cyclins play an important role in cell cycle regulation. At least five classes of cyclins have been identified--A, B, C, D, and E. B cyclins are generally of two types in most organisms--B1 and B2. We have mapped the gene for human cyclin B1 (CCNB1) to human chromosome 5 (region q13-qter) by Southern blot analysis of human x Chinese hamster somatic cell hybrid panels. Many more cyclin B-related sequences have been identified in the mouse (Cycb-1 to Cycb-10) and have been mapped to chromosomes 4, 5, 7, 8, 13, 14, 15, and 17. Based on our mapping of human CCNB1 and known evolutionary conservation of chromosomal regions, we propose that the homologous cyclin B1 locus, Cycb-4, on mouse chromosome 13 is a functional gene.

Animals↗
PubMed1994

The origin of human chromosome 2 analyzed by comparative chromosome mapping with a DNA microlibrary.

Fluorescence in situ hybridization (FISH) of microlibraries established from distinct chromosome subregions can test the evolutionary conservation of chromosome bands as well as chromosomal rearrangements that occurred during primate evolution and will help to clarify phylogenetic relationships. We used a DNA library established by microdissection and microcloning from the entire long arm of human chromosome 2 for fluorescence in situ hybridization and comparative mapping of the chromosomes of human, great apes (Pan troglodytes, Pan paniscus, Gorilla gorilla, Pongo pygmaeus) and Old World monkeys (Macaca fuscata and Cercopithecus aethiops). Inversions were found in the pericentric region of the primate chromosome 2p homologs in great apes, and the hybridization pattern demonstrates the known phylogenetically derived telomere fusion in the line that leads to human chromosome 2. The hybridization of the 2q microlibrary to chromosomes of Old World monkeys gave a different pattern from that in the gorilla and the orang-utan, but a pattern similar to that of chimpanzees. This suggests convergence of chromosomal rearrangements in different phylogenetic lines.

Animals↗
PubMed1976

Basic chromosomal proteins in lower eukaryotes: relevance to the evolution and function of histones.

The occurence of the basic chromosomal proteins in lower eukaryotes provides a useful approach to the study of histone evolution and function in higher eukaryotes. The histones of higher plants and animals are very similar and some are nearly identical, suggesting a high degree of evolutionary conservation within this group of proteins. However, a literature survey reveals that in the lower eukaryotes the histone situation is quite variable. The ciliates, and the true and cellular slime molds possess basic chromosomal proteins that are very similar to the histones of higher plants and animals. Various other lower eukaryotes possess basic chromosomal proteins that resemble at least some of the major histone fractions, and some microorganisms possess basic chromosomal proteins that bear little or no relationship to higher plant and animal histones. Since histones play a major role in the control of gene expression and the maintenance of chromosome structure in higher organisms, the evolution of these proteins represents a major change in the packaging of DNA and the mode of regulating gene expression in eukaryotes.

Animals↗
PubMed1987

Directional fixation of mutations in vertebrate evolution.

We have made pairwise comparisons between the coding sequences of 21 genes from cold-blooded vertebrates and 41 homologous sequences from warm-blooded vertebrates. In the case of 12 genes, GC levels were higher, especially in third codon positions, in warm-blooded vertebrates compared to cold-blooded vertebrates. Six genes showed no remarkable difference in GC level and three showed a lower level. In the first case, higher GC levels appear to be due to a directional fixation of mutations, presumably under the influence of body temperature (see Bernardi and Bernardi 1986b). These GC-richer genes of warm-blooded vertebrates were located, in all cases studied, in isochores higher in GC than those comprising the homologous genes of cold-blooded vertebrates. In the third case, increases appear to be due to a limited formation of GC-rich isochores which took place in some cold-blooded vertebrates after the divergence of warm-blooded vertebrates. The directional changes in the GC content of coding sequences and the evolutionary conservation of both increased and unchanged GC levels are in keeping with the existence of compositional constraints on the genome.

Animals↗
PubMed1996

CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.

Hereditary nonpolyposis colon cancer (HN-PCC) is an autosomally inherited predisposition to cancer that has recently been linked to defects in the human mismatch repair genes hMSH2 and hMLH1. The identification of the causative mutations in HNPCC families is desirable, since it confirms the diagnosis and allows the carrier status of unaffected relatives at risk to be determined. We report six different new mutations identified in the hMSH2 and hMLH1 genes of Russian and Moldavian HNPCC families. Three of these mutations occur in CpG dinucleotides and lead to a premature stop codon, a splicing defect or an amino-acid substitution in an evolutionary conserved residue. Analysis of a compilation of published mutations including our new data suggests that CpG dinucleotides within the coding regions of the hMSH2 and hMLH1 genes are hotspots for single base-pair substitutions.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Monoclonal antibodies to proteins of the myelin-like sheath of earthworm giant axons show cross-reactivity to crayfish CNS glia: an immunogold electron microscopy study.

Monoclonal antibodies were generated to the proteins in myelin-like membranes isolated from the nerve cords of the earthworm, Lumbricus terrestris. One of these showing cross-reactivity to 30-32 and 40 kDa proteins was shown by immunofluorescence microscopy and immunogold electron microscopy to be bound primarily to glial cell process and their membranes and the myelin-like layers. This antibody cross-reacted with proteins of 60-65, 42, and 40 kDa in crayfish (Procambarus clarki) nerve cord homogenates. Localization by immunoelectron microscopy showed the antibody to be bound exclusively to the membranes of the glial processes ensheathing the axons in the crayfish nerve cord. Thus, the proteins in earthworm and crayfish glial cell membranes have some epitopes in common. We suggest that this may represent an evolutionary conservation of these proteins.

Animals↗
PubMed1995

Heat-shock proteins and molecular chaperones: implications for pathogenesis, diagnostics, and therapeutics.

Cells react to physical (e.g., heat) or chemical (e.g., anoxia, low pH) stressors, mounting a stress (heat-shock) response. Most genes are turned down or off, while a few are activated. The latter encode the stress or heat-shock proteins (Hsps), whose levels increase in stressed cells. Various Hsps are molecular chaperones. These, and other molecular chaperones that are not Hsps, help the other cellular proteins to achieve their native state (correct folding or functional conformation), reach their final destination (e.g., the endoplasmic reticulum or the mitochondria), resist denaturing by stressors, and regain the native state after partial denaturation. Thus the Hsps and molecular chaperones occupy the stage's center whenever and wherever there is cellular and tissue injury caused by local or systemic stressors via protein damage. This feature, their participation in protein folding and transport, and their evolutionary conservation within the three phylogenetic domains, strongly suggest a vital role for Hsps and molecular chaperones. Their importance in pathogenesis, and as diagnostic markers and prognostic indicators, is beginning to be appreciated. The role of Hsps and molecular chaperones in cell recovery from injury by a variety of noxae of clinical and surgical relevance is also being assessed. Consequently, the potential of these molecules (and corresponding genes) as targets for treatment or as therapeutic tools is emerging and is being explored. Stroke, myocardial infarction, inflammatory syndromes, infectious and parasitic diseases, autoimmune disorders, cancer, and aging are but some examples of conditions in which Hsps and molecular chaperones are being scrutinized. The era of Hsp and molecular chaperone pathology has dawned. It is likely that genetic and acquired defects of Hsp and molecular chaperone structure and function will be identified, and will play a primary, or auxiliary but determinant, role in disease.

Aging↗